The often aggressive and unpredictable behavior of T-cell malignancies continues to pose major clinical management problems in children and adults. This proposal is based on the central hypothesis that improved understanding of the molecular pathways that contributing to the disordered regulation of cell proliferation, differentiation, and apoptosis in T cell lymphoblastic leukemia and lymphoma (T-ALL/T-LL) will ultimately lead to improved therapy of these diseases. This Program Project Grant (PPG) brings together investigators with expertise in the molecular pathways regulating normal thymocyte development (Drs. von Boehmer, Bassing and Alt), the molecular control of thymocyte cell division (Dr. Sicinski), the regulation of early T cell survival (Drs. von Boehmer, AIt and Look), transcriptional networks regulating development (Drs. Young, Look and von Boehmer), the control of normal and aberrant TCR gene rearrangement (Drs. Bassing and AIt), the molecular pathogenesis of T-cell leukemia and lymphoma in humans (Dr. Look) and in murine models (Drs. Bassing, AIt, Sicinski, and von Boehmer), biostatistics and bioinformatics (Drs. Neuberg and Liu), and gene expression and comparative genomic hybridization (CGH) arrays (Dr. Fox). The research will be accomplished through the coordinated efforts of 4 research projects and 3 cores. In Project 1, Drs. Look and Young will identify downstream target genes within TAL1-mediated transcriptional networks that contribute to the disordered regulation of cell proliferation, differentiation, and apoptosis in human T-cell malignancies. In Project 2, Dr. von Boehmer will investigate the synergy between abnormalities in developmental transcriptional control networks and pre-TCR signaling in the generation of thymic T-LL. In Project 3, Dr. Sicinski will identify how overexpression of TAL1 and LYL1 is connected to the cell cycle machinery in T-ALL cells, specifically to the key cell cycle regulatory cyclins, D3 and D2. In Project 4, Drs. Bassing and AIt will elucidate the molecular mechanisms that lead to chromosomal translocations associated with thymic lymphomas, with focus on pathways involving ATM and H2AX. These projects will be augmented with a Biostatistics Core (Drs Neuberg and Liu), to assist with the analysis of microarray data and the optimal design of animal experiments; a Molecular Core (Dr. Fox) to perform gene expression and comparative genomic hybridization arrays; and an Administrative Core (Drs. Look and von Boehmer), to oversee the administration and coordination of the research interactions among program investigators with expertise in the molecular pathogenesis of human T-LL and T-ALL (Dr Look, Project 1), genome-scale location analysis (Dr. Young, Project 1), T-cell development (Dr. von Boehmer, Project 2), cell cycle regulation (Dr. Sicinski, Project 3), genetic regulation of chromosome stability (Drs. AIt and Bassing, Project 4), gene expression arrays (Drs. Neuberg and Liu, Biostatistics Core, and Dr. Fox, Molecular Core), and computational approaches to the identification of shared binding motifs (Dr. Liu, Biostatistics Core). Such interactions are expected to accelerate the pace at which important discoveries are generated in these projects and in the program as a whole. Successful completion of this 5-year program will improve understanding of how T-cell regulatory pathways are disrupted to initiate and maintain the transformed phenotype in TALL and T-LL, with the long-term goal to pinpoint genes whose inhibition could lead to the development of new and highly specific treatment strategies for these two malignant diseases.